Dendritic cells (DCs) play a pivotal role in the establishment and dissemination of human immunodeficiency virus type 1 (HIV-1) infection as well as in the development of a virus-specific immune response. The involvement of this cell type in the overall pathogenesis of the disease was described soon after the discovery of this retrovirus, but its exact contribution remains elusive.
The mechanism by which HIV-1 is transmitted from the mucosa to CD4+ T cells is not entirely understood. Three possibilities have been proposed to explain how mucosal DCs come in contact with HIV-1. The first proposes a selective transcytosis of R5-tropic virions through the mucosal cells. The second suggests that the initial transmission of R5 virions can occur by infection of mucosal epithelial cells via the galactosylceramide and/or CCR5 receptors. The third alternative promotes the idea that DCs present in the submucosal tissue capture HIV-1 particles with their dendrites. In all three pathways, the crucial events in both virus entry and transmission are the binding and capture of viruses by specific cell surface receptors.
It is now well established that internalization of HIV-1 into target cells requires the formation of a fusion pore resulting from a high-affinity interaction between envelope spike glycoproteins (i.e., gp120) and a complex consisting of the CD4 receptor and a seven-transmembrane coreceptor (e.g., CXCR4 or CCR5). However, it is becoming clear that the initial attachment step is more complex than first thought, since it is modulated by a number of interactions between the viral entity and the target cell surface. The most convincing example is the association between the gp120 oligosaccharides and different C-type lectin receptors, such as mannose receptor (CD206), langerin (CD207), and DC-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN; also called CD209), which are all expressed on DCs. This association results in the capture of HIV-1 and its subsequent transmission to CD4+ T cells, preferentially in a trans-infectious mode.
Following its capture by C-type lectin receptors, a virus particle is rapidly taken up into endolysosomal vacuoles, where it remains infectious for 1 to 3 days, which is approximately the time required for the migration of DCs to the draining lymph nodes. When these DCs encounter CD4+ T cells, the internalized viruses rapidly relocate to the DC-T-cell contact zone, the local region between the two cell types where viruses concentrate, referred to as the virological synapse. Such a close encounter between cells and viruses leads to efficient transfer, subversion of the immune system, and virus production in both cell types, particularly in responder CD4+ T lymphocytes. The reported low levels of CD4, CXCR4, and CCR5 on DCs are probably responsible for their weaker susceptibility to productive HIV-1 infection in vitro compared to that of CD4+ T cells. Interestingly, a recent work has shown that HIV-1 transfer from DCs to CD4+ T cells occurs in two distinct phases. In the initial transfer phase (i.e., early transfer) viruses located within endosomal compartments in DCs are transported to the DC-T-cell synapse as described above. This is followed by a second phase (i.e., late transfer) that is dependent on productive infection of DCs and eventual transfer of progeny virus to CD4+ T cells.
Immature dendritic cells residing in the peripheral tissue such as the epithelial and subepithelial layer of the mucosa are considered the initial targets of HIV. HIV-infected immature dendritic cells then migrate to lymphoid organs and disseminate the virus in the body by either releasing newly synthesized virus or by transmitting the virus to CD4+ T-cells in a trans-infectious mode.
Although C-type lectin such as DC-SIGN participates in the capture of HIV by dendritic cells, it seems that the attachment of HIV to DC-SIGN is not sufficient to allow infection of dendritic cells.
There is thus a need to identify other molecules involved in the early phase of HIV infection.